Isolated aberrant right subclavian artery: an underlying clue for genetic anomalies

Abstract

Objective

Aberrant right subclavian artery (ARSA) is known to be associated with specific chromosomal abnormalities. However, there is no agreement regarding clinical decisions related to isolated ARSA. This study evaluated the association between ARSA and genetic abnormalities to provide evidence for prenatal consultation and the postpartum management of isolated ARSA.

Methods

This single-center cross-sectional study involved fetuses diagnosed with ARSA between January 2014 and May 2021. A range of data was recorded for each patient, including screening ultrasound, fetal echocardiograms, genetic results, postnatal information, and follow-up records.

Results

ARSA was detected in 151 fetuses, of which 136 were considered isolated cases. The remaining 9.9% (15/151) of cases had cardiac and/or extracardiac abnormalities or soft markers. Data from karyotype analysis and chromosomal microarray analysis (CMA) were available for 56 and 33 (out of 56) fetuses, respectively. Genetic abnormalities were detected in 10.7% of fetuses (6/56). Of these, 4.4% (2/45) and 36.4% (4/11) were associated with isolated and non-isolated ARSA, respectively, with a significant difference between these two groups regarding the frequency of genetic abnormality (p = 0.011). The analysis detected Klinefelter Syndrome (47, XXY) and 16p11.2 microdeletion in two isolated cases. One case each of trisomy 21 and 22q11.2 deletion, and another case of 47, XXY, were detected in fetuses with cardiac anomalies. Partial 5q deletion was found in a fetus with extracardiac malformations. In total, 141 of the fetuses survived after birth; termination of pregnancy was performed for 10 fetuses; only two fetuses had mild symptoms of dysphagia.

Conclusion

ARSA may be an underlying ultrasonic clue for genetic anomalies even in isolated ARSA. Fetuses with isolated ARSA cannot be ruled out for invasive antenatal diagnosis.

Keywords:

• Aberrant right subclavian artery
• genetic abnormalities
• chromosomal microarray analysis
• karyotyping

Introduction

Aberrant right subclavian artery (ARSA) is the most frequent anatomical abnormality of the aortic arch, with 1–1.5% in the normal population [1,2]. ARSA is generally associated with anatomical variation [3]. In normal circumstances, the right subclavian artery arises from the brachiocephalic trunk. In contrast, ARSA originates from the superior part of the descending aorta and the distal part of the left subclavian artery. ARSA becomes the last branch of the left aortic arch and crosses behind the esophagus or trachea and up to the right arm. Because of the formation of a U-shaped loop with the descending aorta, ARSA may cause a range of related symptoms, including dysphagia, respiratory distress, and stridor [4,5] when the artery compresses the adjacent esophagus or trachea during the neonatal or infancy stages.

ARSA is more frequent among fetuses with trisomy 21 than in the healthy population [6,7]. Many researchers have described fetuses with ARSA but accompanied by additional cardiac or extracardiac abnormalities; these fetuses have an increased risk for trisomy 21 [8,9]. However, the prevalence of ARSA in fetuses with genetic anomalies, or the prevalence of genetic anomalies in fetuses with ARSA, is yet to be determined [10,11]. Other studies have shown that the presence of ARSA was the only abnormal finding on ultrasound in cases with trisomy 21 [7,12,13]. Furthermore, ARSA has been detected in other less common genetic disorders such as 22q11.2 deletion, 8p23.1 deletion, or Turner syndrome [14–16].

Consequently, there is still a lack of evidence-based management and counseling for women carrying fetuses diagnosed with ARSA, particularly for cases of isolated ARSA. In this study, we investigated the association between ARSA and genetic abnormalities and provide evidence for the prenatal consultation and postpartum management of cases with isolated ARSA.

Materials and methods

This was a retrospective study of all fetuses diagnosed antenatally with ARSA between January 2014 and May 2021 in the Affiliated Hospital of North Sichuan Medical College, China. We included all fetuses diagnosed with ARSA according to fetal echocardiograms in the second and third trimesters, irrespective of low or high-risk pregnancy status. We conducted investigations using a Voluson E8 expert ultrasound system (GE Healthcare, Australia) with targeted prenatal ultrasound by expert fetal echocardiography sonographers. ARSA was detected by analyzing the three-vessels-and-trachea axial view. In these cases, the diagnosis of ARSA was confirmed by ultrasonography postnatally or by pathological examination following induced labor. A range of data was collected for each case from antenatal screening ultrasound (combined cardiac or extracardiac abnormalities and soft markers), fetal echocardiograms, genetic reports, and postnatal records. Chromosomal abnormalities included karyotype abnormalities and pathogenic copy number variation (CNV). Cases were excluded if they were unable to complete follow-up or if there was an incomplete dataset. The Ethics Committee of the Affiliated Hospital of North Sichuan Medical College approved this study (Reference: 2022ER105-1). Each pregnant woman signed a written informed consent document.

Statistical analysis

Statistical analysis was performed with IBM SPSS 22.0 for Windows (SPSS Inc., Chicago, IL). Measured variables are presented as mean ± standard deviation, while categorical variables are presented as numbers and percentages. The Kolmogorov-Smirnov test was used to determine whether the data were normally distributed. The Mann-Whitney U test, Student’s t-test, and Fisher’s exact test compared data between groups. p < 0.05 was deemed statistically significant.

Results

Between January 2014 and May 2021, 148 singleton and three twin pregnancies were identified. At the time of diagnosis, the mean gestational age was 25.9 ± 1.7 weeks, and the median maternal age was 29 years (interquartile range 25–31). ARSA was considered an isolated finding in 136 cases (90.1%, 136 out of 151 cases). There were no other sonographic findings, such as structural malformations and soft markers for these cases. ARSA was associated with other cardiac or extracardiac malformations or soft markers in the remaining 15 cases (9.9%, 15 out of 151 cases). Known outcomes were available for all cases. Of the 151 ARSA fetuses, 10 pregnancies were terminated because of chromosomal and/or structural malformations.

Prenatal diagnosis was confirmed by postnatal echocardiography. Consequently, 141 babies survived after birth, including 132 cases with isolated ARSA and 9 cases with non-isolated ARSA. Two of the 132 babies were born with mild symptoms of dysphagia. Another case underwent surgery because of patent ductus arteriosus 11 months after birth; the other children showed no obvious clinical symptoms. Of the nine fetuses with additional anomalies, eight had a normal clinical phenotype. The one remaining case underwent surgery because of right ureteral obstruction. The clinical features and pregnancy outcomes of fetuses with isolated and non-isolated ARSA are shown in Table 1.

Table 1. The clinical features and pregnancy outcomes associated with isolated and non-isolated ARSA.

	Isolated (n = 136)	Non-isolated (n = 15)	Total (n = 151)	t/Z	P Value
Maternal age, years (median (interquartile range))	28 (26–31)	29 (24–32)	29 (25–31)	−0.041	0.968^a
Gestational age at diagnosis, weeks (mean ± SD)	25.070 ± 2.017	24.830 ± 1.535	24.950 ± 1.749	0.299	0.768^b
Pregnancy outcomes
TOP	4*	6#	10	–	0.000^c
survive	132	9	141

^aMann-Whitney U test; ^bStudent’s t-test; ^cFisher’s exact test.

*Chromosomal abnormalities were found in two out of four cases.

^#Chromosomal abnormalities were found in four out of six cases.

Abbreviation: TOP: termination of pregnancy; ARSA: aberrant right subclavian artery.

Prenatal invasive diagnostic tests were performed in 56/151 (37.1%) fetuses. Of these, 45 cases of ARSA were isolated, and 11 cases were associated with other ultrasonic findings. Karyotype analysis results were available for 56 cases, and chromosomal microarray analysis (CMA) results were available for 33 (out of 56) cases. In total, chromosomal abnormalities were detected in 10.7% (6/56) of fetuses with ARSA, 4.4% (2/45), and 36.4% (4/11) for isolated and non-isolated ARSA, respectively. Compared with non-isolated cases, the frequency of chromosomal abnormality was significantly higher in non-isolated cases (p = 0.011). The chromosomal anomalies included trisomy 21 (Down’s syndrome), 22q11.2 deletion (DiGeorge syndrome), 47, XXY (Klinefelter syndrome), 16p11.2 deletion, and Partial 5q deletion. The analysis detected Klinefelter Syndrome (47, XXY) and 16p11.2 microdeletion in two isolated cases. Both women were 29 years old; the fetuses had no ultrasonic soft markers and showed no increased nuchal translucency (NT) in the first trimester. The distribution of genetic abnormalities in fetuses with ARSA is shown in Table 2.

Table 2. The distribution of chromosomal abnormalities in fetuses with isolated ARSA and non-isolated ARSA.

	Isolated	Non-isolated	Total	p Value
Chromosomal karyotype (n = 56)
abnormalities	1^※	2^#	3	0.011^a
Normal	44	9	53
copy number variation (n = 33)
Pathogenic	1^⋆	2*	3	0.014^a
Normal	26	4	30

※One case of 47, XXY.

⋆One case of 16p11.2 deletion.

# One case each of Trisomy 21 and 47, XXY.

*One case each of 22q11 deletion and Partial 5p deletion.

^aFisher’s exact test.

There were 15/151(9.9%) ARSA cases associated with a cardiac or extracardiac abnormal finding and/or a soft marker. Two cases had an atrioventricular septal defect. Other cardiac ultrasonic findings included ventricular septal defect, persistent left superior vena cava pelvic, and mild tricuspid regurgitation. Extracardiac ultrasonic findings included a pelvic ectopic kidney, cleft lip and palate, ventriculomegaly, clubfeet, cystic hygroma, and increased nuchal translucency. Ultrasonic findings of the six cases with abnormal chromosomal results are presented in Table 3.

Table 3. Ultrasonographic findings of six ARSA fetuses with chromosomal abnormalities.

Case	Maternal age	Chromosomal abnormality	Cardiac abnormalities	Extracardiac abnormalities	Soft marker/ mild anomalies
1	29	47,XXY	_	_	–
2	29	16p11.2 deletion	_	_	–
3	42	Trisomy 21	CAVSD	_	echogenic intracardiac focus
4	30	47, XXY	CAVSD、PLSVA	increased nuchal translucency (NT)	–
5	30	22q11 deletion	VSD	_	mild tricuspid regurgitation
6	34	Partial 5q deletion	_	clubfeet, cystic hygroma	echogenic bowel, slightly seroperitoneum

Abbreviation.

CAVSD: complete atrioventricular septal defect;.

VSD: ventricular septal defect;.

PLSVA: persistent left superior vena cava;.

TOP: termination of pregnancy.

Discussion

In the last decade, many studies have investigated and identified the association between trisomy 21 and ARSA. Yazıcıoğlu et al. reported that 30.4% of 23 fetuses with ARSA also had trisomy 21. The positive and negative likelihood ratios of ARSA for trisomy 21 were 45.08 and 0.65, respectively [17]. Agathokleous et al. proposed that the presence of ARSA was a powerful and independent ultrasound marker for trisomy 21 along with increased nuchal fold, ventriculomegaly, and an absent or hypoplastic nasal bone [18]. Furthermore, ARSA was reported to be the only detectable sign for Down’s syndrome on ultrasound in 8% of cases [19]. However, some studies suggest otherwise. Erzincan et al. analyzed an unselected population and reported that ARSA may occur less frequently than in a high-risk population and may not be associated with Down’s syndrome [20]. In our series of patients, three out of 56 cases (5.3%) were shown to have karyotyping abnormalities. One case of 47, XXY was detected in an isolated case of ARSA. One case of Trisomy 21 and another case of 47, XXY were detected in non-isolated ARSA; these cases also had anatomical abnormalities. These results were consistent with most previous studies. Notably, we detected two cases of 47, XXY in our series. Klinefelter syndrome is a common chromosomal disorder in males (47, XXY) and is associated with various manifestations, including cognitive delays, azoospermia, and specific physical features [21]. This is the first report of a relationship between ARSA and 47, XXY in the literature to the best of our knowledge. Further studies are now required to confirm these findings.

Over recent years, CMA has gradually replaced traditional karyotyping for prenatal diagnosis and can detect CNVs. The 22q11 deletion is the most common pathogenic CNV reported in the literature related to ARSA [10]. The 22q11 deletion syndrome is associated with a broad spectrum of phenotypic features (more than 180), including cardiac defects, developmental abnormalities, thrombocytopenia, psychiatric disorders, and learning disabilities [22–26]. In addition to 22q11 deletion, other pathogenic CNVs have been reported concerning ARSA, including 1q21 duplication and 8p23.1deletion [9,16]. A previous study reported that children and adults with CNVs at 1q21 had high frequencies of psychopathology [27]. In our series, one case of 22q11 deletion and partial 5q deletion was detected in non-isolated ARSA. Furthermore, ARSA was the only prenatal ultrasound finding in a 29-year-old woman carrying a fetus with a 16p11.2 deletion. There are no data in the literature relating to the relationship between 16p11.2 deletion and isolated ARSA. A CNV at the 16p11.2 locus was previously associated with neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia [28–30], leading to intractable phenotypic features and clinical outcomes as the most identified pathogenic CNV-associated ARSA, as described earlier.

Based on chromosomal abnormalities, most researchers recommend invasive testing for complicated cases of ARSA, although opinions differ regarding the management of isolated ARSA. Erzincan et al. suggested that isolated ARSA is not a sufficient indication for karyotype analysis [20]. In another study, Maya et al. reported no indication to perform CMA in a fetus with isolated ARSA [9]. Behram et al. proposed that visualization of the right subclavian artery should be part of the fetal anatomic survey and that genetic analysis should be recommended even in the absence of associated findings [13]. In our study, two of the 56 fetuses with genetic anomalies would likely not have been identified had it not been for the presence of ARSA. In these two cases, ARSA was the only prenatal ultrasound finding that was the only indication for genetic detection because of the lack of other risk factors for genetic anomalies such as advanced age, ultrasonic soft markers, and increased nuchal translucency (NT) in the first trimester. These data imply that ARSA might be an underlying ultrasonic clue for genetic anomalies even in isolated ARSA. Therefore, a detailed scan for ARSA during screening ultrasound would be helpful for other targeted genetic detection.

According to our data, chromosomal anomalies are low (6/56, 10.7%) in ARSA cases. Analysis of published data indicates that ARSA-associated chromosomal abnormalities usually result in a severe and intractable clinical phenotype, even in isolated ARSA. For these reasons, genetic counselors might face even more significant challenges when treating isolated ARSA cases. There are significant challenges regarding the financial burden of pregnant women, balancing the risks of fetal loss because of invasive prenatal diagnosis, and having children with genetic abnormalities. Consequently, we should perform an exhaustive ultrasonic evaluation and specialist genetic consultation before deciding. If the patient is willing to undergo genetic testing, routine karyotyping and CMA should be recommended. Nevertheless, CMA should be recommended for isolated ARSA cases since routine karyotyping may not detect chromosomal micro-variation.

Our study has some limitations. First, this is a cross-sectional study performed in a tertiary referral center. As some fetuses with isolated ARSA may not have been referred to us because of a lack of routine screening in other hospitals or because they were considered irrelevant, we could not calculate the incidence of ARSA in the general population. Moreover, in our series, some fetuses with ARSA were not tested by karyotyping and CMA. Therefore, our ability to acquire a full complement of valuable data was limited. Large-scale, prospective, and multi-center studies are now needed.

Conclusion

In some cases, ARSA might be an underlying antenatal ultrasonic clue for genetic anomalies, leading to adverse clinical outcomes even in isolated ARSA. Cases with isolated ARSA could not be ruled out for invasive antenatal diagnosis in unselected pregnancies, and CMA might be a suitable recommendation for isolated ARSA cases.

Ethical approval

The Ethics Committee of the Affiliated Hospital of North Sichuan Medical College approved this study (Reference: 2022ER105-1). All pregnant women provided informed consent before participating in the study.

Author contributions

RL, QW, XQ participated in the study design. XQ and QS conducted the statistical analysis. RL, QW, XQ, QS, WW, JQ, JH participated in study execution. RL conducted manuscript drafting and critical discussion.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The Special Project for Municipal and University Strategic Cooperation in Science and Technology of Nanchong supported this study [Reference: 20SXQT0069].